This proposal aims to use an animal model to identify genes involved in the development of sperm flagella. Abnormal sperm motility secondary to abnormal flagellar function is found in a subset of males presenting for infertility evaluation. Understanding sperm flagellar assembly will have clinical relevance in understanding the mechanisms of inherited and/or acquired infertility. Equally important will be the insight gained into a closely regulated developmental process. The study of mammalian flagellar biology could be advanced significantly by the characterization of animal lines demonstrating abnormal flagellar morphogenesis. A newly derived transgenic mouse line, ANF/TK, expresses a unique, inherited phenotype involving only the male germ line. The ANF/TK males are infertile, have a normal sperm number and have a spectrum of sperm flagellar abnormalities. I am a Neonatology fellow with a background in research. My perinatal clinical interests lead directly to a research interest in mechanisms of development. Following two intensive clinical years I plan to return to the laboratory to address questions of development. The laboratory of my sponsor, with its emphasis on investigating development using animal models, will provide me with all the resources and technical guidance necessary to address a biological problem at both the whole animal and molecular levels. The specific aims of this research are: (i) to complete a genetic analysis of the inheritance pattern and phenotype of the ANF/TK transgenic line using the techniques of mouse breeding, sperm function testing, electron microscopy and two dimensional gel electrophoresis: (ii) to identify the defect responsible for the infertility using protein isolation and DNA cloning technologies; (iii) to investigate the mechanism of action of the responsible gene(s) an their role(s) in normal murine flagellar assembly, as well as to identify their human homologs.